This invention relates to substituted urea derivatives useful in the treatment of inflammation in joints, central nervous system, gastrointestinal tract, endocardium, pericardium, lung, eyes, ears, skin and urogenital system. More particularly, this invention relates to aryl and heteroaryl substituted sulfonyl ureas that are useful inhibitors of interleukin-1xcex1 and interleukin-1xcex2 processing and release.
IL-1""s status as an important mediator of inflammation Is based on many studies demonstrating this cytokine""s proinflammatory activity. In vivo these effects are manifest as stimulation of cartilage resorption, induction of leukocyte recruitment and the acute phase response, and the production of fever and a shock like state. The changes mediated by IL-1 binding to its receptor include regulation of adhesion molecules and chemokines, stimulation of metalloprotease synthesis, increased synthesis of cyclooxygenase-2 and phospholipase A2 thus increasing prostaglandin production, the induction of nitric oxide synthase thus increasing nitric oxide production and stimulation of IL-6 synthesis resulting in changes in the synthesis of acute phase proteins. Two distinct forms of IL-1 (IL-1xcex1 and IL-1xcex2) are produced by monocytes and macrophages in response to inflammatory stimuli.
The initial translation product of human IL-1xcex2 is a 31 kDa polypeptide that is incompetent to bind to IL-1 receptors on target cells. To promote its biological activity, proIL-1xcex2 first must be cleaved by a thiol protease to generate a 17 kDa mature polypeptide species. This protease, interleukin-1 convertase (ICE), is a member of a novel family of cytosolic proteases that require an aspartic acid residue at the P1 subsite of their substrates. In contrast to proIL-1xcex2, 31 kDa proIL-1xcex1 is competent to bind to IL-1 receptors; nonetheless, this cytokine also is processed to a 17 kDa species by a protease distinct from ICE.
Both forms of IL-1 are synthesized without signal sequences and, as a result, these cytokines accumulate within the cytoplasm of LPS activated monocytes and macrophages. Thus, unlike the majority of secreted cytokines that are processed via the traditional secretory apparatus of the cell involving the endoplasmic reticulum and Golgi apparatus, IL-1 must gain access to the extracellular compartment via a novel secretory pathway. The mechanistic elements of this pathway remain unknown. Recent studies, however, have demonstrated that synthesis of IL-1xcex2 is not coupled to its secretion. Agents that serve as a stimulus to promote IL-1xcex2 posttranslational processing (both proteolytic clevage by ICE and release of the mature 17 kDa species) include ATP, cytolytic Tells, and ionophores such as nigericin. Importantly, LPS-activated murine peritoneal macrophages in vivo also require a secondary stimulus to promote efficient release of mature IL-1xcex2, and ATP was demonstrated to serve in this capacity. Thus, IL-1xcex2 production is highly regulated both in vitro and in vivo by requiring separate stimuli to promote transcription, translation, and posttranslational maturation/release.
Therapeutic approaches that seek to inhibit ICE as a means to regulate production of IL-1 are likely to be limited because ICE inhibitors: 1) do not block release of proIL-1xcex2 which could be processed extracellularly by other proteases to generate a mature biolgically active cytokine species, and 2) do not decrease production of IL-1xcex1 by activated monocytes/macrophages. Therefore, atherapeutic approach that prevents activation of the posttranslational processing and release of IL-1 is likely to provide efficacy superior to that of an ICE inhibitor by blocking externalization of both cytokine species.
Mammalian cells capable of producing IL-1 include, but are not limited to, karatinocytes, endothelial cells, mesangial cells, thymic epithelial cells, dermal fibroblasts, chondrocytes, astrocytes, glioma cells, mononuclear phagocytes, granulocytes, T and B lymphocytes and NK cells.
The activities of interleukin-1 are many. Subcutaneous injection of IL-1 leads to fever, sleepiness, anorexia, generalized myalgias, arthralgias, headache, and, on increasing exposure, hypotension. Margination of neutrophils and maximal extravascular infiltration of the polymorphonuclear leukocytes (PMN) is also observed. IL-1 also stimulates chondrocytes to release matrix metalloproteases, resulting in the degredation of cartilage matrix.
Accordingly, disease states in which the IL-1 processing and release inhibitors of Formula 1 may be useful as therapeutic agents include, but are not limited to, infectious diseases where active infection exists at any body site, such as meningitis and salpingitis; complication of infections including septic shock, disseminated intravascular coagulation, and/or adult respiratory distress syndrome; acute or chronic inflammation due to antigen, antibody and/or complement deposition; inflammatory conditions including arthritis, cholangitis, colitis, encephalitis, endocarditis, glomerulonephritis, hepatitis, myocarditis, pancreatitis, pericarditis, reperfusion injury and vasculitis. Immune-based diseases which may be responsive to IL-1 processing and release inhibitors of Formula 1 include but are not limited to conditions involving T-cells and/or macrophages such as acute and delayed hypersensitivity, graft rejection, and graft-versus-host disease; auto-immune diseases including Type 1 diabetes mellitus and multiple sclerosis. IL-1 processing and release inhibitors of Formula 1 may also be useful in the treatment of bone and cartilage resorption as well as diseases resulting in excessing deposition of extracellular matrix. Such diseases include periodonate diseases, interstitial pulmonary fibrosis, cirrhosis, systemic sclerosis and keloid formation. IL-1 processing and release inhibitors of Formula 1 may also be useful in treatment of certain tumors which produce IL-1 as an autocrine growth factor and in preventing the cachexia associated with certain tumors. IL-1 processing and release inhibitors of Formula 1 may also be useful in the treatment of neuronal diseases with an inflammatory component, including, but not limited to Alzheimers disease, depression and percussion injury. IL-1 processing and release inhibitors may also be useful in treating cardiovascular diseases in which recruitment of monocytes into the subendothelial space plays a role, such as the development of atherosclerotic placques.
The present invention relates to a compound of the formula 
or a pharmaceutically acceptable salt thereof, wherein
R1 is (C1-C6)alkyl optionally substituted by (C1-C6)alkylamino, (C1-C6)alkylthio, (C1-C6)alkoxy, trifluoromethyl, (C6-C10)aryl, (C5-C9)heteroaryl, (C5-C10)arylamino, (C6-C10)arylthio, (C6-C10)aryloxy, (C5-C9)heteroarylamino, (C5-C9)heteroarylthio, (C5-C9)heteroaryloxy, (C6-C10)aryl(C6-C10)aryl, (C3-C6)cycloalkyl, hydroxy(C1-C6)alkyl, (C1-C6)alkyl(hydroxymethylene),piperazinyl, (C6-C10)aryl(C1-C6)alkoxy, (C5-C9)heteroaryl(C1-C6)alkoxy, (C1-C6)acylamino, (C1C6)acylthio, (C1-C6)acyloxy, (C1-C6)alkylsulfinyl, (C6-C10)arylsulfinyl, (C1-C6)alkylsulfonyl, (C6-C10)arylsulfonyl, amino, (C1-C6)alkylamino or ((C1-C6)alkyl)2amino; or
R1 and R2 are each independently a group of the formula 
wherein the broken lines represent optional double bonds;
n is 0, 1, 2 or 3;
A, B,- D, E-and -G -are- each-independently-oxygen, sulfur, nitrogen or CR5R6 wherein R5 and R6 are each independently selected from hydrogen, (C1-C6)alkyl optionally substituted by one or two groups selected from (C1-C1)alkylamino, (C1-C6)alkylthio, (C1-C6)alkoxy, hydroxy, cyano, perfluoro(C1-C6)alkyl, (C6-C10)aryl, (C5-C9)heteroaryl, (C6-C10)arylamino, (C6-C10)arylthio, (C6-C10)aryloxy wherein the aryl group is optionally substituted by (C1-C6)alkoxy, (C1-C6)acyl, carboxy, hydroxy or halo; (C5-C9)heteroarylamino,(C5-C9)heteroarylthio,(C5-C9)heteroaryloxy,(C6-C10)aryl(C6-C10)aryl, (C3-C5)cycloalkyl, hydroxy, piperazinyl, (C6-C10)aryl(C1-C6)alkoxy, (C5-C9)heteroaryl(C1-C6)alkoxy, (C1-C6)acylamino, (C1-C6)acylthio, (C1-C6)acyloxy, (C1-C6)alkylsulfinyl, (C6-C10)arylsulfinyl, (C1-C6)alkylsulfonyl, (C6-C10)arylsufonyl, amino, (C1-C6)alkylamino or ((C1-C6)alkyl)2amino; halo, cyano, amino, hydroxy, perfluoro(C1-C6)alkyl, perfluoro(C1-C6)alkoxy, (C2-C6)alkenyl, carboxy(C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkylamino,((C1-C6)alkyl)2amino, (C1-C6)alkylsulfonylamido, (C1-C6)alkylsulfinyl, aminosulfonyl, (C1-C6)alkylaminosulfonyl, ((C1-C6)alkyl)2aminosulfonyl, (C1-C6)alkylthio, (C1-C6)alkoxy, perfluoro(C1-C6)alkyl, (C6-C10)aryl, (C5-C9)heteroaryl, (C6-C10)arylamino, (C6-C10)arylthio, (C6-C10)aryl(C1-C6)alkoxy, (C5-C9)heteroarylamino, (C5-C9)heteroarylthio, (C5-C9)heteroaryloxy, (C3-C6)cycloalkyl, (C1-C6)alkyl(hydroxymethylene), piperidyl, pyridinyl, thienyl, furanyl, (C1-C6)alkylpiperidyl, (C1-C6)acylamino, (C1-C6)acylthio, (C1-C6)acyloxy, R7(C1-C6)alkyl wherein R7 is (C1-C6)acylpiperazino, (C6-C10)arylpiperazino, (C5-C9)heteroarylpiperazino, (C1-C6)alkylpiperazino, (C6-C10)aryl(C1-C6)alkylpiperazino, (C5-C9)heteroaryl(C1-C6)alkylpiperazino, morpholino,thiomorpholino, piperidino, pyrrolidino, piperidyl, (C1-C6)alkylpiperidyl, (C6-C10)arylpiperidyl, (C5-C9)heteroarylpiperidyl, (C1-C6)alkylpiperidyl(C1-C6)alkyl, (C6-C10)arylpiperidyl(C1-C6)alkyl, (C5-C9)heteroarylpiperidyl(C1-C6)alkyl or (C1-C6)acylpiperidyl;
or a group of the formula 
wherein s is 0 to 6;
t is 0 or 1;
X is oxygen or NR8 wherein R8 is hydrogen, (C1-C6)alkyl or (C3-C7)cycloalkyl(C1-C6)alkyl;
Y is hydrogen, hydroxy, (C1-C6)alkyl, optionally substituted by halo, hydroxy or cyano; (C1-C6)alkoxy, cyano, (C2-C6)alkynyl, (C6-C10)aryl wherein the aryl group is optionally substituted by halo, hydroxy, carboxy, (C1-C6)alkyl, (C1-C6)alkoxy; perfluoro(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl or NR9R10 wherein R9 and R10 are each independently selected from the group consisting of hydrogen, (C1-C6)alkyl optionally substituted by (C1-C6)alkylpiperidyl, (C6-C10)arylpiperidyl, (C5-C9)heteroarylpiperidyl, (C6-C10)aryl, (C5-C9)heteroaryl or (C3-C6)cycloalkyl; piperidyl, (C1-C6)alkylpiperidyl, (C6-C10)arylpiperidyl, (C5-C9)heteroarylpiperidyl, (C1-C6)acylpiperidyl, (C6-C10)aryl, (C5-C9)heteroaryl, (C3-C6)cycloalkyl, R11(C2-C6)alkyl, (C1-C6)alkyl wherein R11 is hydroxy, (C1-C6)cycloalkyl,(C1-C6)alkoxy, piperzino, (C1-C6)acylamino, C1-C6)alkylthio,(C6-C10)arylthio,(C1-C6)alkyluslfinyl,(C6-C10)arylsulfinyl,(C1-C6)alkylsulfoxyl, (C6-C10)arylsulfoxyl, amino, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, (C1-C6)acylpiperazino, (C1-C6)alkylpiperazino, (C6-C10)aryl(C1-C6)alkylpiperazino, (C5-C9)heteroaryl(C1-C6)alkylpiperazino, morpholino, thiomorpholino, piperidino or pyrrolidino; R12(C1-C6)alkyl, (C1-C5)alkyl(CHR12)(C1-C6)alkyl wherein R12 is piperidyl or (C1-C6)alkylpiperidyl; and CH(R13)COR14 wherein R14 is as defined below and R13 is hydrogen, (C1-C6)alkyl, (C6-C10)aryl(C1-C5)alkyl, (C5-C9)heteroaryl(C1-C6)alkyl, (C1-C6)alkylthio(C1-C6)alkyl, (C6-C10)arylthio(C1-C6)alkyl, (C1-C6)alkylsulfinyl(C1-C6)alkyl, (C6-C10)arylsulfinyl(C1-C6)alkyl, (C1-C6)alkylsulfonyl(C1-C6)alkyl, (C6-C10)arylsulfonyl(C1-C6)alkyl, hydroxy(C1-C6)alkyl, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, ((C1-C6)alkylamino)2(C1-C6)alkyl, R15R16NCO(C1-C6)alkyl or R15OCO(C1-C6)alkyl wherein R15 and R16 are each independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl and (C5-C9)heteroaryl(C1-C6)alkyl; and R14 is R17O or R17R18N wherein R17 and R18 are each independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl and (C5-C9)heteroaryl(C1-C9)alkyl;
or a group of the formula 
wherein u is 0, 1 or 2;
R19 is hydrogen, (C1-C6)alkyl or perfluoro(C1-C6)alkyl;
R20 is hydrogen, (C1-C6)alkyl, (C1-C6)carboxyalkyl or (C6-C10)aryl(C1-C6)alkyl;
or a group of the formula 
wherein a is 0, 1 or 2;
b is 0 or 1;
c is 1, 2 or 3;
d is 0 or 1;
e is 0, 1 or 2;
J and L are each independently oxygen or sulfur;
R21 is hydrogen, hydroxy, fluoro, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, amino, (C1-C6)acylamino or NR25R27 wherein R26 and R27 are each independently selected from hydrogen, (C1-C6)alkyl or (C6-C10)aryl; and
R22 is hydrogen, (C1-C6)alkyl optionally substituted by hydroxy, halo, (C1-C6)alkylthio, (C1-C6)alkylsulfinyl or (C1-C6)alkylsulfonyl;
or when n is 1 and B and D are both CR5, the two R5 groups may be taken together with the carbons to which they are attached to form a group of the formula 
wherein the broken lines represent optional double bonds;
m is 0 or 1; and
T, U, V and W are each independently oxygen, sulfur, CO, nitrogen or CR5R6 wherein R5 and R6 are as defined above;
or when A and B, or when n is 1 and B and D, or D and E, or E and G, are both CR5, the two R5 groups may be taken together with the adjacent carbons to which they are attached to form a (C5-C6)cycloalkyl group optionally substituted by hydroxy or a benzo group;
or when n is 1 and D and E are both CR5, the two R5 groups may be taken together with the adjacent carbons to which they are attached to form a group of the formula 
wherein the broken line represents an optional double bond;
R23 is hydrogen, (C1-C6)alkyl, halo, amino or (C1-C6)alkoxy;
J is C or SO;
K is oxygen, NR24 wherein R24 is hydroxy, (C1-C6)alkoxy or (C6-C10)aryl(C1-C6)alkoxy; or hydroxy;
or R25SO2 wherein R25 is defined as R1 above or (C3-C7)cycloalkylamino; and
with the proviso that the groups of formulas II and VI cannot have two oxygens, two sulfurs or an oxygen and sulfur defined in adjacent positions;
with the proviso that R2 must be aromatic;
with the proviso that when either a or e is 0, the other must be 1;
with the proviso that when b and d are 1, the sum of a, c and e cannot be 6 or 7; and
with the proviso that when A, B, D, E, G, T, U, V and W represent an sp2 carbon, R6 does not exist.
The term xe2x80x9calkylxe2x80x9d, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof.
The term xe2x80x9calkoxyxe2x80x9d, as used herein, includes O-alkyl groups wherein xe2x80x9calkylxe2x80x9d is defined above.
The term xe2x80x9carylxe2x80x9d, as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl, optionally substituted by 1 to 3 substituents selected from the group consisting of fluoro, chloro, trifluoromethyl, (C1-C6)alkoxy, (C6-C10)arytoxy, trifluoromethoxy, difluoromethoxy and (C1-C6)alkyl.
The term xe2x80x9cheteroarylxe2x80x9d, as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic heterocyclic compound by removal of one hydrogen, such as pyridyl, furyl, pyroyl, thienyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, indolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benzthiazolyl or benzoxazolyl, optionally substituted by 1 to 2 substituents selected from the group consisting of fluoro, chloro, trifluoromethyl, (C1-C6)alkoxy, (C6-C10)aryloxy, trifluoromethoxy, difluoromethoxy and (C1-C6)alkyl.
The term xe2x80x9cacylxe2x80x9d, as used herein, unless otherwise indicated, includes a radical of the general formula RCO wherein R is alkyl, alkoxy, aryl, arylalkyl or arylalkyloxy and the terms xe2x80x9calkylxe2x80x9d or xe2x80x9carylxe2x80x9d are as defined above.
The term xe2x80x9cacyloxyxe2x80x9d, as used herein, includes O-acyl groups wherein xe2x80x9cacylxe2x80x9d is defined above.
Preferred compounds of formula I include those wherein R1 is a group of the formula 
wherein the broken lines represent double bonds;
n is 0 is 1;
A is CR5 wherein R5 is hydrogen or halo;
B and E are both independently CR5 wherein R5 is hydrogen cyano, halo, (C1-C6)alkyl optionally substituted by one or two hydroxy; (C3-C7)cycloalkylaminosulfonyl, (C1-C6)alkylaminosulfonyl, or a group of the formula 
wherein s is 0;
t is 0; and
Y is hydrogen, (C1-C6)alkyl optionally substituted by halo; or (C1-C6)alkoxy(C1-C6)alkyl;
or a group of the formula 
wherein a is 0 or 1;
b is 0 or 1;
c is 1 or 2;
d is 0 or 1;
c is 0 or 1;
J and L are each independently oxygen or sulfur;
R21 is hydrogen, hydroxy or (C1-C6)alkyl optionally substituted by halo; and
R22 is hydrogen or (C1-C6)alkyl optionally substituted by hydroxy, halo, (C1-C6)alkylthio, (C1-C6)alkylsulfinyl or (C1-C6)alkylsulfonyl;
or group of the formula 
wherein u is 0 or 1;
R19 is (C1-C6)alkyl or trifluoromethyl; and
R20 is hydrogen;
D is CR5 wherein R5 is hydrogen, (C1-C6)alkyl or halo;
G is CR5 wherein R5 is oxygen, sulfur or CR5 wherein R5 is hydrogen or halo;
or when n is 1 and B and D are both CR5, the two R5 groups may be taken together with the carbons to which they are attached to form a group of the formula 
wherein the broken lines represent double bonds;
m is 0;
T is oxygen, nitrogen or CR5 wherein R5 is hydrogen;
U is CO or CR5 wherein R5 is hydrogen; and
W is nitrogen or CR5 wherein R5 is hydrogen;
or when n is 1 and D and E are both CR5, the two R5 groups may be taken together with the adjacent carbons to which they are attached to form a group of the formula 
wherein the broken line represents an optional double bond;
R23 is hydrogen or (C1-C6)alkyl;
J is C or SO
K is oxygen, NR24 wherein R24 is hydroxy; or hydroxy.
Other preferred compounds of formula I include those wherein R2 is a group of the formula 
wherein the broken lines represent optional double bonds;
n is 1;
A is CR5 wherein R5 is halo or (C1-C6)alkyl;
B is CR5 wherein R5 is hydrogen or halo;
D is CR5 wherein R5 is hydrogen, halo, cyano or a group of the formula 
wherein S is 0;
t is 0; and
Y is NH2;
E is CR5 wherein R5 is hydrogen or halo; and
G is CR5 wherein R5 is halo or (C1-C6)alkyl;
or when A and B, or E and G, are both CR5, the two R5 groups may be taken together with the adjacent carbons to which they are attached to form a (C5-C6)cycloalkyl group.
Other preferred compounds of formula I include those wherein R1 is a group of the formula 
wherein the broken lines represent double bonds;
n is 0 is 1;
A is CR5 wherein R5 is hydrogen or halo;
B and E are both independently CR5 wherein R5 is hydrogen cyano, halo, (C1-C6)alkyl optionally substituted by one or two hydroxy; (C3-C7)cycloalkylaminosulfonyl, (C1-C6)alkylaminosulfonyl, or a group of the formula 
wherein s is 0;
t is 0; and
Y is hydrogen, (C1-C6)alkyl optionally substituted by halo; or (C1-C6)alkoxy(C1-C6)alkyl;
or a group of the formula 
wherein a is 0 or 1;
b is 0 or 1;
c is 1 or 2;
d is 0 or 1;
c is 0 or 1;
J and L are each independently oxygen or sulfur;
R21 is hydrogen, hydroxy or (C1-C6)alkyl optionally substituted by halo; and
R22 is hydrogen or (C1-C6)alkyl optionally substituted by hydroxy, halo, (C1-C6)alkylthio, (C1-C6)alkylsulfinyl or (C1-C6)alkylsulfonyl;
or a group of the formula 
wherein u is 0 or 1;
R19 is (C1-C6)alkyl or trifluoromethyl; and
R20 is hydrogen;
D is CR5 wherein R5 is hydrogen, (C1-C6)alkyl or halo;
G is CR5 wherein R5 is oxygen, sulfur or CR5 wherein R5 is hydrogen or halo;
or when n is 1 and B and D are both CR5, the two R5 groups may be taken together with the carbons to which they are attached to form a group of the formula 
wherein the broken lines represent double bonds;
m is 0;
T is oxygen, nitrogen or CR5 wherein R5 is hydrogen;
U is CO or CR5 wherein R5 is hydrogen; and
W is nitrogen or CR5 wherein R5 is hydrogen;
or when n is 1 and D and E are both CR5, the two R5 groups may be taken together with the adjacent carbons to which they are attached to form a group of the formula 
wherein the broken line represents an optional double bond;
R23 is hydrogen or (C1-C6)alkyl;
J is C or SO
K is oxygen, NR24 wherein R24 is hydroxy; or hydroxy; and
R2 is a group of the formula 
wherein the broken lines represent optional double bonds;
n is 1;
A is CR5 wherein R5 is halo or (C1-C6)alkyl;
B is CR5 wherein R5 is hydrogen or halo;
D is CR5 wherein R5 is hydrogen, halo, cyano or a group of the formula 
wherein s is 0;
t is 0; and
Y is NH2;
E is CR5 wherein R5 is hydrogen or halo; and
G is CR5 wherein R5 is halo or (C1-C6)alkyl;
or when A and B, or E and G, are both CR5, the two R5 groups may be taken together with the adjacent carbons to which they are attached to form a (C5-C6)cycloalkyl group.
Specific preferred compounds of formula I include the following:
1-(4-Chloro-2,6-diisopropyl-phenyl)-3-[3-(1-hydroxy-1-methyl-ethyl)-benzenesulfonyl]-urea;
1-(1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)-3-[4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonyl]-urea;
1-(1,2,3,5,6,7-Hexahydro-4-aza-s-indacen-8-yl)-3-[4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonyl]-urea;
1-(1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)-3-[4-(1-hydroxy-1-methyl-ethyl)-thiophene-2-sulfonyl]-urea;
1-(4-[1,3]Dioxolan-2-yl-furan-2-sulfonyl)-3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-urea;
1-(2,6-Diisopropyl-phenyl)-3-[4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonyl]-urea;
1-(2,6-Diisopropyl-phenyl)-3-[4-(1-hydroxy-1-methyl-ethyl)-thiophene-2-sufonyl]-urea;
1-(4-Acetyl-thiophene-2-sulfonyl)-3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-urea;
1-(1H-Benzoimidazole-5-sulfonyl)-3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-urea;
1-(1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)-3-[4-(1-hydroxy-1-methyl-ethyl)-thiophene-2-sulfonyl]-urea;
1-(8-Chloro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[4-(1-hydroxy-1-methylthyl)-furan-2-sulfonyl]urea;
1-(4-Acetyl-furan-2-sulfonyl)-3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-urea;
1-(8-Fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonyl]-urea;
1-(4-Fluoro-2,6-diisopropyl-phenyl)-3-[3-(1-hydroxy-1-methyl-ethyl)-benzenesulfonyl]-urea;
1-(6-Fluoro-1H-benzoimidazole-5-sulfonyl)-3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-urea;
1-(4-Chloro-2,6-diisopropyl-phenyl)-3-(1H-indole-6-sulfonyl)-urea;
1-(4-Chloro-2,6-diisopropyl-phenyl)-3-(5-fluoro-1H-indole-6-sulfonyl)-urea;
1-[1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)-3-(1H-indole-6-sulfonyl)-urea;
1-(5-Fluoro-1H-indol-6-sulfonyl)-3-(1,2,3,5,6,7-hexanhydro-5-indacen-4-yl)-urea;
1-[4-Chloro-2,6-diisopropyl-phenyl]-3-[2-fluoro-5-(2-methyl-(1,3)dioxolan-2-yl)-benzenesulfonyl]urea;
3-[3-[4-Chloro-2,6-diisopropyl-phenyl]-ureidosulfonyl]-N-methyl-benzenesulfonamide;
1-[2-Fluoro-5-(2-methyl-(1,3)dioxolan-2-yl)benzenesulfonyl]-3-1,2,3,5,6,7-hexahydro-indacen-4-yl)-urea; and
3-[3-(1,2,3,5,6,7-Hexahydro-S-indacen-4-yl)-ureidosulfonyl]-N-methyl-benzenesulfonamide.
The present invention also relates to a pharmaceutical composition for the treatment of meningitis and salpingitis, septic shock, disseminated intravascular coagulation, and/or adult respiratory distress syndrome, acute or chronic inflammation, arthritis, cholangitis, colitis, encephalitis, endocarditis, glomerulonephritis, hepatitis, myocarditis, pancreatitis, pericarditis, reperfusion injury, vasculitis, acute and delayed hypersensitivity, graft rejection, and graft-versus-host disease, auto-immune diseases including Type 1 diabetes mellitus and multiple sclerosis, periodonate diseases, interstitial pulmonary fibrosis, cirrhosis, systemic sclerosis, keloid formation, tumors which produce IL-1 as an autocrine growth factor, cachexia, Alzheimers disease, percussion injury, depression, atherosclerosis (including cardiomyopathy, myocarditis and heart failure)-and-osteoporosis in a mammal, including a human comprising administering an amount of a compound of formula I or a pharmaceutically acceptable salt thereof, effective in such treatments or inhibition and a pharmaceutically acceptable carrier.
The present invention also relates to a method for treating a condition selected from the group consisting of meningitis and salpingitis, septic shock, disseminated intravascular coagulation, and/or adult respiratory distress syndrome, acute or chronic inflammation, arthritis, cholangitis, colitis, encephalitis, endocarditis, glomerulonephritis, hepatitis, myocarditis, pancreatitis, pericarditis, reperfusion injury, vasculftis, acute and delayed hypersensitivity, graft rejection, and graft-versus-host disease, auto-immune diseases including Type 1 diabetes mellitus and multiple sclerosis, periodonate diseases, interstitial pulmonary fibrosis, cirrhosis, systemic sclerosis, keloid formation, tumors which produce IL-1 as an autocrine growth factor, cachexia, Alzheimers disease, percussion injury, depression, atherosclerosis (including cardiomyopathy, myocarditis and heart failure) and osteoporosis in a mammal, including a human, comprising administering to said mammal an amount of a compound of formula I or a pharmaceutically acceptable salt thereof, effective in treating such a condition.
The following reaction Schemes illustrate the preparation of the present invention. Unless otherwise indicated n, A, B, D, E and G in the reaction Schemes and the disussion that follow are defined as above. 
In reaction 1 of Preparation A, the compound of formula XII is converted to the corresponding isocyanate compound of formula Xi by reacting XII with triphosgene in the presence of a base, such as triethylamine, diisopropylethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene, and a aprotic solvent, such as tetrahydrofuran, benzene or methylene chloride. The mixture is stirred and heated to reflux for a time period between about 1 hour to about 3 hours, preferably about 2 hours.
In reaction 1 of Preparation B, the compound of formula XIV is converted to the corresponding sulfonamide compound of formula XIII by adding an alkyllithium, such as n-butyl, sec-butyl or tert-butyl lithium, to a stirred solution of XIV in a polar solvent, such as tetrahydrofuran, at a temperature between about xe2x88x9270xc2x0 C. to about xe2x88x9285xc2x0 C., preferably about xe2x88x9278xc2x0 C. After approximately 15 minutes, liquified sulfur dioxide is added to the reaction mixture so formed, stirred at approximately xe2x88x9278xc2x0 C. for 5 minutes and then warmed to room temperature for a time period between about 1 hour to about 3 hours, preferably about 2 hours. The mixture is then (a) concentrated in vacuo, and treated with either a chlorinating reagent, such as N-chloro-succinimide in a polar solvent, such as methylene chloride, followed by treatment with gasous or aqueous ammonia or (b) treated with hydroxylamine o-sulfonic acid in water in the presence of a buffer, such as sodium acetate.
In reaction 1 of Preparation C, the compound of formula XVI is converted to the corresponding sulfonamide compound of formula XV by adding a solution of sodium nitrate in water to a stirred solution of XVI in a mixture acetic acid and hydrochloric acid. Acetic acid saturated with sulfur dioxide gas is then added followed by cuprous chloride. The reaction mixture so formed is stirred at a temperature between about xe2x88x9210xc2x0 C. to about 10xc2x0 C., preferably about 0xc2x0 C., for a time period between about 1 hour to about 3 hours, preferably about 2 hours. The resulting sulfonyl chloride is then treated with gasous or aqueous ammonia bubbled through a solution of the sulfonyl chloride in an aprotic solvent, such as methylene chloride or ether.
In reaction 1 of Preparation D, the compound of formula XVIII is converted to the corresponding sulfonamide compound of formula XVII by reacting XVIII with chlorosulfonic acid in a polar aprotic solvent, such as chloroform at a temperature between about xe2x88x92100xc2x0 C. to about 10xc2x0 C., preferably about 0xc2x0 C. The reaction mixture so formed is warmed to approximately 60xc2x0 C. After a time period between about 1.5 hours to about 2.5 hours, preferably about 2 hours, the reaction mixture is once again cooled to a temperature approximately 0xc2x0 C. and poured onto ice. The resulting sulfonyl chloride is then treated with gasseous or aqueous ammonia bubbled through a solution of the sulfonyl chloride n an aprotic solvent such as methylene chloride or ether.
In reaction 1 of Scheme 1, the isocyanate compound of formula X and the sulfonamide compound of formula IX are converted to the corresponding sulfonyl urea compound of formula VII by reacting IX and X in the presence of a base, such as sodium hydride, sodium hydroxide, triethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene, and a polar solvent, such as tetrahydrofuran, acetone or dimethylformamide. The reaction mixture so formed is heated to reflux for a time period between about 10 hours to about 14 hours, preferably about 12 hours.
Mononuclear cells are purified from 100 ml of blood isolated using LSM (Organon Teknika). The heparinized blood (1.5 ml of 1000 units/ml heparin for injectin from Apotheconis added to each 50 ml syringe) is diluted with 20 ml of Medium (RMI 1640, 5% FBS, 1% pen/strep, 25 mM HEPES, pH 7.3). 30 ml of the diluted blood is layered over 15 ml of LSM (Organon Teknika) In a 50 ml conical polypropylene centrifuge tube. The tubes are centrifuged at 1200 rpm for 30 minutes in benchtop Sorvall centrifuge at room temperature. The mononuclear cells, located at the interface of the plasma and LSM, are removed, diluted with Medium to achieve a final volume of 50 ml, and collected by centrifugation as above. The supernatant is discarded and the cell pellet is washed 2 times with 50 ml of medium. A 10 xcexcl sample of the suspended cells is taken before the second wash for counting; based on this count the washed cells are diluted with medium to a final concentration of 2.0xc3x97106 cells/ml.
0.1 ml of the cell suspension is added to each well of 96 well plates. The monocytes are allowed to adhere for 2 hours, then non-adherent cells are removed by aspiration and the attached cells are washed twice with 100 xcexcl f Medium. 100 xcexcl of Medium is added to each well, and the cells are incubated overnight at 37xc2x0 C. in a 5% carbon dioxide incubator.
The following day, 25 xcexcl of 50 ng/ml LPS (in Medium) is added to each well and the cells are activated for 2 hours at 37xc2x0 C.
Test agents are diluted with dimethyl sulfoxide to a final concentration of 10 mM. From this stock solution compounds are first diluted 1:50 [5 xcexcl of 10 mM stock+245 xcexcl Chase Medium (RPMI 1640, 25 mM Hepes, pH 6.9, 1% FBS, 1% pen/strep, 10 ng/ml LPS and 5 mM sodium bicarbonate]. A second dilution is prepared by adding 10 xcexcl of the 200 xcexcM test agent to 90 xcexcl of Chase Medium yielding a final concentration of 20 xcexcM test agent; the dimethyl sulfoxide concentration at this point is 0.2%.
The LPS-activated monocytes are washed once with 100 xcexcl of Chase Medium then 100 xcexcl of Chase Medium (containing-0.2% dimethyl sulfoxide) is added to each well. 0.011 ml of the 20 xcexcM test agent solutions are added to the appropriate wells, and the monocytes are incubated for 30 minutes at 37xc2x0 C. At this point 2 mM ATP is introduced by adding 12 xcexcl of a 20 mM stock solution (previously adjusted to pH 7.2 with sodium hydroxide) and the cells are incubated for an additional 3 hours at 37xc2x0 C.
The 96-well plates are centrifuged for 10 minutes at 2000 rpm in a Sorvall benchtop centrifuge to remove cells and cell debris. A 90 xcexcl aliquot of each supernatant is removed and transferred to a 96 well round bottom plate and this plate is centrifuged a second time to ensure that all cell debris is removed. 30 xcexcl of the resulting supernatant is added to a well of an IL-18 ELISA plate that also contains 70 xcexcl of PBS, 1% FBS. The ELISA plate is incubated overnight at 4xc2x0 C. The ELISA (RandD Systems) is run following the kit kirections. Data Calculation and Analysis:
The amount of IL-1xcex2 immunoreactivity in the chase medium samples is calculated as follows:
% control=(X-B)/(TOT-B)xc3x97100
where X=OD450 nm of test compound well
B=OD450 of Reagent Blank wells on the ELISA
TOT=O.D450 of cells that were treated with 0.2% dimethyl sulfoxide only.
The compounds of the present invention can be administered in a wide variety of different dosage forms, in general, the therapeutically effective compounds of this invention are present in such dosage forms at concentration levels ranging from about 5.0% to about 70% by weight.
For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelation and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
For parenteral administration (intramuscular, intraperitoneal, subcutaneous and intravenous use) a sterile injectable solution of the active ingredient is usually prepared. Solutions of a therapeutic compound of the present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed. The aqueous solutions should be suitably adjusted and buffered, preferably at a pH of greater than 8, if necessary and the liquid diluent first rendered isotonic. These aqueous solutions are suitable intravenous injection purposes. The oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.